ABSTRACT Undifferentiated sarcomas are the most aggressive types of sarcoma, often metastatic, with a very poor prognosis. Although it has been established that undifferentiated sarcomas originate from Mesenchymal Stem Cells (MSCs), limited genetic and molecular analyses, along with the absence of faithful in vivo models enabling pre-clinical testing are the main reasons why the development of effective therapies has not yet occurred. To fill this void, we have recently developed a novel ex vivo/in vivo MSCs-based genetic platform aimed at discovering the molecular drivers responsible for adult MSC tumorigenesis, and to test, in pre-clinical settings, new potential druggable pathways. An initial screening performed by using this genetic-platform, has revealed a new function for Pokemon (Zbtb7a) as an oncosuppressor in mesenchymal tumors through the protein-mediated repression of the oncogenes Sox9 and Dlk1. Furthermore, the platform revealed for the first time that circRNAs, in addition to proteins, can be responsible for mesenchymal tumors. We discovered that the circRNA that derives from the Zbtb7a gene (circPOK) plays an active role as a proto-oncogene in the process of mesenchymal tumorigenesis, and moreover we discovered that aberrant fusion-circRNAs (f- circRNAs) can derive from sarcoma-associated chromosomal translocations. These new findings add a further layer of complexity in the biology of cancer, revealing new possible intragenic regulatory networks that can be perturbed in pathological conditions, and point to the necessity to investigate if, and how, other circRNAs are involved in sarcomagenesis. Taking together our recent results and our previously developed genetic platform, we now propose: i) to perform a wide-ranging analysis of genetic and molecular drivers of mesenchymal tumors, encompassing coding-genes, circRNAs, and f-circRNAs, ii) to analyze the molecular mechanisms of action directed by these drivers, and iii) to identify new therapies to cure mesenchymal tumors. Accordingly we propose the following aims: Identification of new protein-coding genes (Aim 1), identification of circRNAs (Aim 2) and identification of f-circRNAs (Aim 3) that drive mesenchymal tumorigenesis. During the K99 phase, I will obtain the skills required to begin my independent career. In this phase, I will develop assays and protocols to characterize the functions of circRNAs and f-circRNAs, which will be then used during the R00 phase. Moreover in the K99 phase, I will perform a screening analysis, with a particular interest to potential new druggable mechanisms. Candidate genes resulting from the screening will be then closely analyzed during the R00 phase. The work performed during the K99 phase will be the groundwork for the next R00 phase. As such, the mentoring will be necessary element of the K99 phase in order to achieve solid and valid results.